Ignite Creation Date:
2024-05-05 @ 11:46 PM
Last Modification Date:
2024-10-26 @ 10:39 AM
Study NCT ID:
NCT01412892
Status:
COMPLETED
Last Update Posted:
2014-11-14
First Post:
2011-08-08
Brief Title:
Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
A Single Arm Multicenter Phase II a Trial of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas That Cannot be Removed by Surgery
Status:
COMPLETED
Status Verified Date:
2014-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NFitor
Brief Summary:
Background
Patients with the genetic disorder neurofibromatosis Type 1 NF1 are at increased risk of developing tumors of the central and peripheral nervous system These include plexiform neurofibromas The conventional treatment of these internal plexiform neurofibromas is surgery This surgery can be possible on a single and limited tumor On the other hand these tumors are often surgically intractable due to their multiplicity and their infiltrating characteristics Increased activity of mammalian target of rapamycinmTOR protein is seen in neurofibromas mTOR inhibitor rapamycin or its derivatives such as everolimus may slow or stop tumor growth in patients with NF1
Objectives
Primary objectives To determine whether everolimus has an effect on the volume of surgically intractable and life-threatening internal plexiform neurofibromas in patients with neurofibromatosis 1
Secondary objectives To determine whether everolimus has an effect on the number and the volume of cutaneous neurofibromas to determine whether everolimus modify the signaling pathways in cutaneous neurofibromas
Eligibility
- Adults with neurofibromatosis type 1 with at least one internal plexiform neurofibroma life-threatening or causing significant morbidity through compression of organs This or these internal plexiform neurofibromas should be intractable by surgery
Design
An open-label single arm non-randomized single stage phase IIa study Baseline phase Baseline evaluations will be performed within 2 weeks and up to a maximum of 4 weeks for specific exams before the first dose of study drug
Treatment phaseduration of treatment All patients will be treated with RAD001 10 mg po daily dose for one year except in case of unacceptable toxicity death or discontinuation from the study for any other reason
Follow-up phase All patients will have two follow-up visits scheduled at 18 and 24 months after the first dose of the study drug to follow for adverse events AEs and serious adverse events SAEs that may have occurred after discontinuation from the study and for internal plexiform neurofibromas assessment
Radiological review All Magnetic Resonance Imaging MRIs obtained at baseline during the treatment period and the follow-up period will be reviewed by the Neuroradiologist of the study
Patients with the genetic disorder neurofibromatosis Type 1 NF1 are at increased risk of developing tumors of the central and peripheral nervous system These include plexiform neurofibromas The conventional treatment of these internal plexiform neurofibromas is surgery This surgery can be possible on a single and limited tumor On the other hand these tumors are often surgically intractable due to their multiplicity and their infiltrating characteristics Increased activity of mammalian target of rapamycinmTOR protein is seen in neurofibromas mTOR inhibitor rapamycin or its derivatives such as everolimus may slow or stop tumor growth in patients with NF1
Objectives
Primary objectives To determine whether everolimus has an effect on the volume of surgically intractable and life-threatening internal plexiform neurofibromas in patients with neurofibromatosis 1
Secondary objectives To determine whether everolimus has an effect on the number and the volume of cutaneous neurofibromas to determine whether everolimus modify the signaling pathways in cutaneous neurofibromas
Eligibility
- Adults with neurofibromatosis type 1 with at least one internal plexiform neurofibroma life-threatening or causing significant morbidity through compression of organs This or these internal plexiform neurofibromas should be intractable by surgery
Design
An open-label single arm non-randomized single stage phase IIa study Baseline phase Baseline evaluations will be performed within 2 weeks and up to a maximum of 4 weeks for specific exams before the first dose of study drug
Treatment phaseduration of treatment All patients will be treated with RAD001 10 mg po daily dose for one year except in case of unacceptable toxicity death or discontinuation from the study for any other reason
Follow-up phase All patients will have two follow-up visits scheduled at 18 and 24 months after the first dose of the study drug to follow for adverse events AEs and serious adverse events SAEs that may have occurred after discontinuation from the study and for internal plexiform neurofibromas assessment
Radiological review All Magnetic Resonance Imaging MRIs obtained at baseline during the treatment period and the follow-up period will be reviewed by the Neuroradiologist of the study
Detailed Description:
Neurofibromatosis 1 NF1 is an autosomal dominant disease affecting 1 in 3000 to 1 in 4000 people NF1 is characterized by multiple dermal neurofibromas plexiform neurofibromas malignant peripheral nerve sheath tumors MPNST and optic pathway gliomas as well as by café-au-lait spots and abnormalities of the skeletal cardiovascular and central nervous systems The NF1 gene is located on chromosome 17q112 and its protein neurofibromin functions as a tumor suppressor
People with NF1 have a decrease in life expectancy of 15 years with MPNST as a leading cause of death in young adults A specific phenotype at risk of mortality has been identified patients with subcutaneous neurofibromas Individuals with subcutaneous neurofibromas are more than 3 times as likely to have internal plexiform neurofibromas as others Individuals with internal plexiform neurofibromas are 18 times more likely to develop MPNST than patients without internal plexiform neurofibromas Beside MPNST internal plexiform neurofibromas can be life-threatening or cause of significant morbidity through compression of organs mainly spine or nerve roots
The conventional treatment of these internal plexiform neurofibromas is surgery This surgery can be possible on a single and limited tumor On the other hand these tumors are often surgically intractable due to their multiplicity and their infiltrating characteristics In this context a medical treatment decreasing the size of these tumors would have its place with as short term aim to lower the consequence of compression and long-term aim to reduce the risk of malignant transformation
NF1 is a consequence of the loss-of-function mutations in the NF1 tumor suppressor gene The NF1-encoded protein neurofibromin functions as a Ras-GTPase activating protein RasGAP Accordingly deregulation of Ras is thought to contribute to NF1 development The mTOR pathway is tightly regulated by neurofibromin mTOR is constitutively activated in both NF1-deficient primary cells and human tumors in the absence of growth factors This aberrant activation depends on Ras and PI3 kinase and is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT Importantly tumor cell lines derived from NF1 patients and a genetically engineered cell system that requires Nf1-deficiency for transformation are highly sensitive to the mTOR inhibitor rapamycin Furthermore the activation of endogenous Ras leads to constitutive mTOR signaling in this disease state and in normal cells Ras is differentially required for mTOR signaling in response to various growth factors Thus the NF1 tumor suppressor is an indispensable regulator of TSC2 and mTOR Ras plays a critical role in the activation of mTOR in both normal and tumorigenic settings
mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model In these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression including inhibition of HIF-1 alpha and indirect suppression of AKT but does suppress the mTOR target Cyclin D1 The mammalian target of rapamycin complex 1 inhibitor RAD001 Everolimus decreased growth 19 to 60 after 4 days of treatment in NF1 MPNST cell lines
Finally these data suggest that rapamycin or its derivatives such as everolimus may represent a viable therapy for NF1 This proof of concept has been done in tuberous sclerosis where rapamycin was efficient to treat angiomyolipomas11
The management of neurofibromatoses in France is coordinated by Pr Pierre WOLKENSTEIN through the French National Referral Centre for Neurofibromatoses and a network NF-France The cohort followed up by the centre and its network is constituted of about 3000 patients and among them between 80 and 100 have life-threatening internal plexiform neurofibromas
Therefore the investigators propose a trial to evaluate the efficacy of everolimus in surgically intractable and life-threatening internal neurofibromas in neurofibromatosis 1 based on the data of the literature and on our cohort
People with NF1 have a decrease in life expectancy of 15 years with MPNST as a leading cause of death in young adults A specific phenotype at risk of mortality has been identified patients with subcutaneous neurofibromas Individuals with subcutaneous neurofibromas are more than 3 times as likely to have internal plexiform neurofibromas as others Individuals with internal plexiform neurofibromas are 18 times more likely to develop MPNST than patients without internal plexiform neurofibromas Beside MPNST internal plexiform neurofibromas can be life-threatening or cause of significant morbidity through compression of organs mainly spine or nerve roots
The conventional treatment of these internal plexiform neurofibromas is surgery This surgery can be possible on a single and limited tumor On the other hand these tumors are often surgically intractable due to their multiplicity and their infiltrating characteristics In this context a medical treatment decreasing the size of these tumors would have its place with as short term aim to lower the consequence of compression and long-term aim to reduce the risk of malignant transformation
NF1 is a consequence of the loss-of-function mutations in the NF1 tumor suppressor gene The NF1-encoded protein neurofibromin functions as a Ras-GTPase activating protein RasGAP Accordingly deregulation of Ras is thought to contribute to NF1 development The mTOR pathway is tightly regulated by neurofibromin mTOR is constitutively activated in both NF1-deficient primary cells and human tumors in the absence of growth factors This aberrant activation depends on Ras and PI3 kinase and is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT Importantly tumor cell lines derived from NF1 patients and a genetically engineered cell system that requires Nf1-deficiency for transformation are highly sensitive to the mTOR inhibitor rapamycin Furthermore the activation of endogenous Ras leads to constitutive mTOR signaling in this disease state and in normal cells Ras is differentially required for mTOR signaling in response to various growth factors Thus the NF1 tumor suppressor is an indispensable regulator of TSC2 and mTOR Ras plays a critical role in the activation of mTOR in both normal and tumorigenic settings
mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model In these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression including inhibition of HIF-1 alpha and indirect suppression of AKT but does suppress the mTOR target Cyclin D1 The mammalian target of rapamycin complex 1 inhibitor RAD001 Everolimus decreased growth 19 to 60 after 4 days of treatment in NF1 MPNST cell lines
Finally these data suggest that rapamycin or its derivatives such as everolimus may represent a viable therapy for NF1 This proof of concept has been done in tuberous sclerosis where rapamycin was efficient to treat angiomyolipomas11
The management of neurofibromatoses in France is coordinated by Pr Pierre WOLKENSTEIN through the French National Referral Centre for Neurofibromatoses and a network NF-France The cohort followed up by the centre and its network is constituted of about 3000 patients and among them between 80 and 100 have life-threatening internal plexiform neurofibromas
Therefore the investigators propose a trial to evaluate the efficacy of everolimus in surgically intractable and life-threatening internal neurofibromas in neurofibromatosis 1 based on the data of the literature and on our cohort
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2010-023137-34 | EUDRACT_NUMBER | None | None |